title: Repression of inflammasome by Francisella tularensis during early stages of infection.
abstract: Francisella tularensis is an important human pathogen responsible for causing tularemia. F. tularensis has long been developed as a biological weapon and is now classified as a category A agent by the Centers for Disease Control because of its possible use as a bioterror agent. F. tularensis represses inflammasome; a cytosolic multi-protein complex that activates caspase-1 to produce proinflammatory cytokines IL-1β and IL-18. However, the Francisella factors and the mechanisms through which F. tularensis mediates these suppressive effects remain relatively unknown. Utilizing a mutant of F. tularensis in FTL_0325 gene, this study investigated the mechanisms of inflammasome repression by F. tularensis. We demonstrate that muted IL-1β and IL-18 responses generated in macrophages infected with F. tularensis live vaccine strain (LVS) or the virulent SchuS4 strain are due to a predominant suppressive effect on TLR2-dependent signal 1. Our results also demonstrate that FTL_0325 of F. tularensis impacts proIL-1β expression as early as 2 h post-infection and delays activation of AIM2 and NLRP3-inflammasomes in a TLR2-dependent fashion. An enhanced activation of caspase-1 and IL-1β observed in FTL_0325 mutant-infected macrophages at 24 h post-infection was independent of both AIM2 and NLRP3. Furthermore, F. tularensis LVS delayed pyroptotic cell death of the infected macrophages in an FTL_0325-dependent manner during the early stages of infection. In vivo studies in mice revealed that suppression of IL-1β by FTL_0325 early during infection facilitates the establishment of a fulminate infection by F. tularensis. Collectively, this study provides evidence that F. tularensis LVS represses inflammasome activation and that F. tularensis-encoded FTL_0325 mediates this effect.
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, New York 12208, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Dotson
authors.forename: Seham M
authors.initials: SM
authors.lastname: Rabadi
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Westcott
authors.forename: Stephen
authors.initials: S
authors.lastname: Bradley
authors.forename: Sally V
authors.initials: SV
authors.lastname: Catlett
authors.forename: Sukalyani
authors.initials: S
authors.lastname: Banik
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Harton
authors.forename: Chandra Shekhar
authors.initials: CS
authors.lastname: Bakshi
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malik
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death; D004268:DNA-Binding Proteins; D005604:Francisella tularensis / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014406:Tularemia / Q000276:immunology* / Q000382:microbiology*
chemical_list: C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016899:Interferon-beta
keywords: Bacterial Pathogenesis; Cytokine; Francisella; Il-1b; Immune Subversion; Immunosuppression; Inflammasome; Inflammation; Macrophages